Strength in Numbers?
CREDIT: NEIL J. GANEM/BOSTON UNIVERSITY
Some mammalian cells are loaded with extra sets of chromosomes, a state called polyploidy. What on Earth for? A dividing cell generally follows a simple rule. After duplicating its DNA, the cell splits, yielding two daughter cells. That’s why the movies of dividing mouse liver cells shot several years ago by Andrew Duncan, then a postdoc in Markus Grompe’s group at the Oregon Health & Science University in Portland, flabbergasted his lab mates. “We saw a single cell giving rise to three and four daughter cells,” says Duncan, who is now a tissue biologist at the University of Pittsburgh in Pennsylvania. And though chromosomes normally line up neatly across the middle of a cell before it divides, the chromosomes in many of the liver cells were arranged in unconventional formations, including multiple clusters. The parental liver cells were forced to go through unusual maneuvers because they were polyploid, carrying extra sets of chromosomes. Polyploidy is rife among plants, insects, fish, and some other groups of organisms. But most human cells are diploid, outfitted with two sets of chromosomes that trace back to the set each provided by an egg and a sperm. Indeed, extra chromosomes usually spell trouble in mammalian cells. A few normal cells in people and other mammals, however, brim with extra genome copies—sometimes as many as a thousand. The contortions of the liver cells were surprising, but they had long been known to have a surfeit of chromosomes—as do cells in the heart and bone marrow. For decades, researchers have speculated about whether polyploidy offers any advantages to mammalian cells, such as
ramping up protein synthesis, but haven’t to polyploidy. “It can drive cancer,” been able to test their ideas. That has changed says David Pellman, a cell biologist and with the identification of several proteins pediatric oncologist at the Dana-Farber that help regulate polyploidy. By cranking Cancer Institute in Boston. He points to a cells’ allotment of chromosomes up or down, 2013 Nature Genetics paper by Rameen scientists recently have begun to explore the Beroukhim, also of Dana-Farber, and possible function of the odd cellular state. Do colleagues that reported duplicated the extra chromosomes simply add bulk to genomes in 37% of cancers. Polyploidy cells that need it? Do they give cells reserve doesn’t lead to cancer in every case, capacity that enables them to respond to stress Pellman says, but it’s a big enough risk that and damage? “The real unanswered question many cells go to great lengths to thwart it. is why any cell type is polyploid,” p53, the watchful protein dubbed says developmental geneticist the guardian of the genome, often Robert Duronio of the University prompts cells with abnormal of North Carolina (UNC), sciencemag.org amounts of DNA to commit Podcast interview Chapel Hill. “We are poised to suicide or to curtail division. To with editor John begin answering that question.” become polyploid, therefore, Travis (http://scim.ag/ And even though the mystery pod_6172). cells have to disable it and other of polyploidy’s benefits remains safeguards that protect against unsolved, some researchers already hope genome damage, notes biologist Gustavo to exploit the phenomenon. They are trying Leone of Ohio State University, Columbus. to turn polyploidy against certain cancers, Researchers have gradually acquired a compelling cells to cease their out-of- good grasp of the molecules and mechanisms control division. that make cells polyploid, thanks mainly to their work on the cell cycle. A cell’s life cycle Risky excess includes milestones such as DNA dupliPolyploidy can seem like “a dangerous cation and division. An intricate network of escapade,” as Duronio and his colleagues proteins controls the cell’s progress through put it in a 2009 paper. For cells that usually the cycle, pushing it forward or holding it get along just fine with two sets of chro- back. Under the right circumstances, mosomes, even one additional chromo- researchers have found, some of these some can be disastrous. An extra copy of proteins steer cells toward polyploidy. chromosome 21 during development proTo tweak the chromosome content of duces the disabilities of Down syndrome, cells, several research teams have recently for instance. genetically engineered mice to make more There’s another potential drawback or less of these polyploidy promoters.
Online
www.sciencemag.org SCIENCE VOL 343 Published by AAAS
14 FEBRUARY 2014
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Downloaded from www.sciencemag.org on February 13, 2014
A little extra. A human cell with twice the normal number of chromosomes (white) attempts to divide.
NEWSFOCUS For example, biochemist Katya Ravid of Boston University School of Medicine and colleagues enhanced polyploidy to test its role in megakaryocytes, hefty immune cells that dwell in the bone marrow and generate the platelets that help stanch bleeding. Megakaryocytes often harbor more than 100 copies of their genome, and researchers conjectured that the extra genes help the cells crank out platelets. In 2010, Ravid’s team engineered mice to manufacture excess amounts of a polyploidy-promoting protein. Although the alteration boosted the number of
ber 2013 issue of the Proceedings of the National Academy of Sciences. Researchers already have evidence from other species that extra heft is a benefit of polyploidy. In a 2012 study of fruit flies, Terry Orr-Weaver of the Massachusetts Institute of Technology and her colleague Yingdee Unhavaithaya found that when they reduced the levels of a polyploidystimulating protein in cells forming the blood-brain barrier in flies, the cells shrank and the barrier became leaky. The pair also showed that enlarging the undersized cells restored a tight seal. Boosting the size of
Deep reserves For the heart and the liver, two hard-working organs that also teem with polyploid cells, researchers are exploring a different explanation for polyploidy: The extra chromosomes boost performance under trying conditions and increase overall resilience. Indeed, “polyploidy may be an important stress response or adaptation” for many cell types, says cell biologist Donald Fox of Duke University Medical Center in Durham, North Carolina. Support for that notion comes from a study of the mouse heart, in which almost all the cells sport four sets of chromosomes. In 2010,
P O LY P L O I D C E L L T Y P E S I N M A M M A L S C CEELLLL TTYYPPEE
LLO OC CAT ATIIO ON N
FFU UN NC CTTIIO ON N
N NU UM MB BEERR O OFF G GEEN NO OM MEE C CO OPPIIEESS
Megakaryocyte
Bone marrow
Producing blood clotting platelets
Up to 128
Hepatocyte
Liver
Detoxification, metabolism
Typically 4 to 16
Trophoblast giant cell
Embryo
Promote implantation
Up to 1000
Cardiomyocyte
Heart
Contraction
Typically 4
chromosome sets the cells contained, it didn’t cause a corresponding rise in platelet numbers, the team revealed in The Journal of Biological Chemistry. Ravid suggests that polyploidy instead benefits megakaryocytes by boosting production of proteins that the cells need for structural support and sticking to their neighbors. Bulking up Biophysical engineer Dennis Discher of the University of Pennsylvania School of Medicine offers another explanation. He suspects that polyploidy helps a megakaryocyte in the same way a high-calorie diet helps a sumo wrestler—by increasing bulk. A membrane perforated by small pores separates the bone marrow from the bloodstream, and a megakaryocyte has to stay on the bone marrow side. Discher and his colleagues recently examined what size pores different types of bone marrow cells could slip through, and they found that megakaryocytes had trouble squeezing through even the largest openings, probably because of their chromosomepacked nuclei. “If you ask me why this cell is polyploid, I’d say it helps anchor the body of the cell in the marrow,” says Discher, whose team reported its findings in the 19 Novem-
726
multiple chromosome copies (blue) have sorted into three clusters in preparation for cell division.
existing cells might cause less disruption than producing more cells through division, which requires that a cell disengage from its neighbors, notes cell biologist Brian Calvi of Indiana University, Bloomington. Yet for one mammalian cell type that takes polyploidy to the extreme, work by Leone’s team downplays the size connection. Cells in the outer layer of embryos, known as trophoblast giant cells, are polyploidy champions—in mice they pack up to 1000 genome copies. The cells help the embryo implant in its mother’s womb, and researchers have suggested that adding chromosomes allows the cells to quickly enlarge, enabling the embryo to infiltrate the uterine lining. Leone and his colleagues deleted genes for polyploidy-promoting proteins from trophoblast giant cells in mice, anticipating that embryos would die because implantation would suffer. “We were expecting that polyploidy is really significant,” Leone says. Although the giant trophoblast cells were smaller than normal and carried fewer chromosomes, the mouse embryos lived and grew up into seemingly healthy adults, the researchers reported in Nature Cell Biology in 2012.
14 FEBRUARY 2014
stem cell biologist Thomas Braun of the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, and colleagues examined genetically altered mice whose muscle cells—including those in the heart— were missing a gene that spurs polyploidy. Although the gene’s absence didn’t make all the animals’ heart cells diploid, it did reduce the number of chromosome sets they contained by about one-third. “At baseline conditions, they are pretty normal,” Braun says of the mice. However, deficiencies appeared when the rodents had to cope with setbacks such as a heart attack. The hearts of animals with reduced polyploidy pumped less blood after an induced heart attack than did the hearts of control animals, the group reported in Circulation Research. How polyploidy enables the heart to rebound remains unclear, Braun says. The work by Duncan and his colleagues on liver cells also backs the stress-response hypothesis. Unlike most mammalian organs, the liver has a remarkable ability to regenerate after injury. The liver is also well stocked with polyploid cells: In humans, about 50% of the liver cells called hepatocytes carry extra sets of chromosomes. Duncan’s team had originally explored
VOL 343 SCIENCE www.sciencemag.org Published by AAAS
CREDIT: (RIGHT) ANDREW W. DUNCAN AND MARKUS GROMPE
Bonus DNA. The polyploid cells in mammalian bodies differ in their location, function, and number of chromosome sets (table). In a liver cell (right), the
CREDIT: A. DUNCAN ET AL., GASTROENTEROLOGY 6 (JANUARY 2012) © 2012 AGA INSTITUTE, PUBLISHED BY ELSEVIER INC.
NEWSFOCUS whether the polyploid cells within the liver are “terminally differentiated,” meaning that they had become mature cells that don’t divide and help replenish the organ. So the team transplanted polyploid hepatocyte cells into mice whose livers had been partially removed. “To our great surprise, they regenerated the liver perfectly,” Duncan says. That’s when Duncan put the liver cells under the microscope, turned on the camera, and noticed their unorthodox division style. The researchers discovered something else unusual about the cells. As the team revealed in Nature in 2010, when many of the polyploid cells divided, they spawned diploid daughter cells. But often these diploid daughters hadn’t quite returned to normal—many of them had gained or lost an individual chromosome, a condition called aneuploidy that is generally considered ominous. “Most cancer folks will Double down. The chromosome copies from a polyploid liver cell arranged by size, showing that the cell tell you that aneuploidy is synonymous with carries four copies of almost every one. cancer,” Duncan says. But some researchers have proposed their livers were no less able to regrow after who develop it. Mature megakaryocytes that aneuploidy can create useful genetic injury. The mice De Bruin and colleagues don’t divide, but in this form of cancer, the diversity in a tissue or organ, allowing cells studied, for example, could restore their livers cells remain immature, don’t become polyto add a copy of a beneficial gene or throw after surgical removal of two-thirds of the ploid, and replicate prodigiously, causing out a copy of a detrimental one. And when organ. “This polyploidization does not have the leukemia. Crispino and colleagues proDuncan and colleagues studied an example an effect on regeneration or on proliferation pose that forcing the cells to become polyof liver regeneration in mice, they found that rate,” De Bruin says. ploid and mature might treat the cancer. sites where regrowth occurred were rich in The work from both teams also underThe team revealed in Cell in 2012 that aneuploid cells. They have discovered that mines another older polyploidy hypothesis. it had identified more than 200 compounds aneuploid cells are abundant in human The liver, De Bruin notes, “is all the time that, in lab dishes, spur polyploidy in livers, too. human megakaryocytes. One Duncan now hypothesizes of these molecules, alisertib, that polyploidy in the liver is is already under-going clinical The real unanswered question is why any a roundabout way to produce trials for several other types of aneuploid cells that have cancer—though not because cell type is polyploid. We are poised to regenerative properties. His team of its ability to stimulate begin answering that question. is now working to confirm that polyploidy. Crispino’s group is these cells spur regeneration in now trying to organize an initial —Robert Duronio, University of North Carolina, Chapel Hill people suffering from hepatitis safety trial of the drug in people B, in which a virus devastates the with acute myeloid leukemia. liver. Some patients die unless they get a liver exposed to toxins.” Hepatocytes work hard Although polyploidy research has recorded transplant, but others survive as sections of to detoxify all those noxious substances, some progress in recent years, the field still the organ regenerate. The researchers are and some researchers had speculated that hasn’t nailed down the benefits polyploidy collecting tissue samples to determine if their extra genetic material could boost the provides to different mammal cell types. areas of the liver that regrow are high in output of proteins crucial to this. Yet the mice To move forward, Leone says, researchers aneuploid cells. whose livers had reduced polyploidy had no should take a cue from plant biologists, But the idea that polyploidy helps tissues problems breaking down toxins, De Bruin’s who have tested polyploidy’s advantages in regenerate remains a hypothesis, as findings group found. specific environmental conditions, showing from Leone’s group and that of Alain de that it boosts tolerance for salinity (Science, Bruin, a pathologist and veterinarian at Exploiting polyploidy 9 August 2013, p. 658). Scientists could Utrecht University in the Netherlands, Even as they wrestle with mystery of poly- perform similar studies on liver cells, for emphasize. They genetically engineered mice ploidy, researchers wonder whether they example, by gauging whether polyploidy so the animals’ livers lack two polyploidy- can put what they’ve learned to use. Leu- helps them deal with different diets. Delving promoting proteins. “We can generate a kemia biologist John Crispino of North- further into polyploidy’s cellular roles will mouse whose liver is almost entirely [diploid] western University’s Feinberg School of probably produce some surprises, UNC cells,” De Bruin says. Both teams expected Medicine in Chicago, Illinois, and his col- Chapel Hill’s Duronio predicts. “There are that the animals would suffer ill effects. leagues have trained their sights on a type going to be many uses for polyploidy, and Instead, the mice were vigorous, each group of acute myeloid leukemia, triggered by we are just scratching the surface.” reported in Nature Cell Biology in 2012, and megakaryocytes, that kills most adults –MITCH LESLIE www.sciencemag.org SCIENCE VOL 343 Published by AAAS
14 FEBRUARY 2014
727
CREDIT: NEIL J. GANEM/BOSTON UNIVERSITY
Some mammalian cells are loaded with extra sets of chromosomes, a state called polyploidy. What on Earth for? A dividing cell generally follows a simple rule. After duplicating its DNA, the cell splits, yielding two daughter cells. That’s why the movies of dividing mouse liver cells shot several years ago by Andrew Duncan, then a postdoc in Markus Grompe’s group at the Oregon Health & Science University in Portland, flabbergasted his lab mates. “We saw a single cell giving rise to three and four daughter cells,” says Duncan, who is now a tissue biologist at the University of Pittsburgh in Pennsylvania. And though chromosomes normally line up neatly across the middle of a cell before it divides, the chromosomes in many of the liver cells were arranged in unconventional formations, including multiple clusters. The parental liver cells were forced to go through unusual maneuvers because they were polyploid, carrying extra sets of chromosomes. Polyploidy is rife among plants, insects, fish, and some other groups of organisms. But most human cells are diploid, outfitted with two sets of chromosomes that trace back to the set each provided by an egg and a sperm. Indeed, extra chromosomes usually spell trouble in mammalian cells. A few normal cells in people and other mammals, however, brim with extra genome copies—sometimes as many as a thousand. The contortions of the liver cells were surprising, but they had long been known to have a surfeit of chromosomes—as do cells in the heart and bone marrow. For decades, researchers have speculated about whether polyploidy offers any advantages to mammalian cells, such as
ramping up protein synthesis, but haven’t to polyploidy. “It can drive cancer,” been able to test their ideas. That has changed says David Pellman, a cell biologist and with the identification of several proteins pediatric oncologist at the Dana-Farber that help regulate polyploidy. By cranking Cancer Institute in Boston. He points to a cells’ allotment of chromosomes up or down, 2013 Nature Genetics paper by Rameen scientists recently have begun to explore the Beroukhim, also of Dana-Farber, and possible function of the odd cellular state. Do colleagues that reported duplicated the extra chromosomes simply add bulk to genomes in 37% of cancers. Polyploidy cells that need it? Do they give cells reserve doesn’t lead to cancer in every case, capacity that enables them to respond to stress Pellman says, but it’s a big enough risk that and damage? “The real unanswered question many cells go to great lengths to thwart it. is why any cell type is polyploid,” p53, the watchful protein dubbed says developmental geneticist the guardian of the genome, often Robert Duronio of the University prompts cells with abnormal of North Carolina (UNC), sciencemag.org amounts of DNA to commit Podcast interview Chapel Hill. “We are poised to suicide or to curtail division. To with editor John begin answering that question.” become polyploid, therefore, Travis (http://scim.ag/ And even though the mystery pod_6172). cells have to disable it and other of polyploidy’s benefits remains safeguards that protect against unsolved, some researchers already hope genome damage, notes biologist Gustavo to exploit the phenomenon. They are trying Leone of Ohio State University, Columbus. to turn polyploidy against certain cancers, Researchers have gradually acquired a compelling cells to cease their out-of- good grasp of the molecules and mechanisms control division. that make cells polyploid, thanks mainly to their work on the cell cycle. A cell’s life cycle Risky excess includes milestones such as DNA dupliPolyploidy can seem like “a dangerous cation and division. An intricate network of escapade,” as Duronio and his colleagues proteins controls the cell’s progress through put it in a 2009 paper. For cells that usually the cycle, pushing it forward or holding it get along just fine with two sets of chro- back. Under the right circumstances, mosomes, even one additional chromo- researchers have found, some of these some can be disastrous. An extra copy of proteins steer cells toward polyploidy. chromosome 21 during development proTo tweak the chromosome content of duces the disabilities of Down syndrome, cells, several research teams have recently for instance. genetically engineered mice to make more There’s another potential drawback or less of these polyploidy promoters.
Online
www.sciencemag.org SCIENCE VOL 343 Published by AAAS
14 FEBRUARY 2014
725
Downloaded from www.sciencemag.org on February 13, 2014
A little extra. A human cell with twice the normal number of chromosomes (white) attempts to divide.
NEWSFOCUS For example, biochemist Katya Ravid of Boston University School of Medicine and colleagues enhanced polyploidy to test its role in megakaryocytes, hefty immune cells that dwell in the bone marrow and generate the platelets that help stanch bleeding. Megakaryocytes often harbor more than 100 copies of their genome, and researchers conjectured that the extra genes help the cells crank out platelets. In 2010, Ravid’s team engineered mice to manufacture excess amounts of a polyploidy-promoting protein. Although the alteration boosted the number of
ber 2013 issue of the Proceedings of the National Academy of Sciences. Researchers already have evidence from other species that extra heft is a benefit of polyploidy. In a 2012 study of fruit flies, Terry Orr-Weaver of the Massachusetts Institute of Technology and her colleague Yingdee Unhavaithaya found that when they reduced the levels of a polyploidystimulating protein in cells forming the blood-brain barrier in flies, the cells shrank and the barrier became leaky. The pair also showed that enlarging the undersized cells restored a tight seal. Boosting the size of
Deep reserves For the heart and the liver, two hard-working organs that also teem with polyploid cells, researchers are exploring a different explanation for polyploidy: The extra chromosomes boost performance under trying conditions and increase overall resilience. Indeed, “polyploidy may be an important stress response or adaptation” for many cell types, says cell biologist Donald Fox of Duke University Medical Center in Durham, North Carolina. Support for that notion comes from a study of the mouse heart, in which almost all the cells sport four sets of chromosomes. In 2010,
P O LY P L O I D C E L L T Y P E S I N M A M M A L S C CEELLLL TTYYPPEE
LLO OC CAT ATIIO ON N
FFU UN NC CTTIIO ON N
N NU UM MB BEERR O OFF G GEEN NO OM MEE C CO OPPIIEESS
Megakaryocyte
Bone marrow
Producing blood clotting platelets
Up to 128
Hepatocyte
Liver
Detoxification, metabolism
Typically 4 to 16
Trophoblast giant cell
Embryo
Promote implantation
Up to 1000
Cardiomyocyte
Heart
Contraction
Typically 4
chromosome sets the cells contained, it didn’t cause a corresponding rise in platelet numbers, the team revealed in The Journal of Biological Chemistry. Ravid suggests that polyploidy instead benefits megakaryocytes by boosting production of proteins that the cells need for structural support and sticking to their neighbors. Bulking up Biophysical engineer Dennis Discher of the University of Pennsylvania School of Medicine offers another explanation. He suspects that polyploidy helps a megakaryocyte in the same way a high-calorie diet helps a sumo wrestler—by increasing bulk. A membrane perforated by small pores separates the bone marrow from the bloodstream, and a megakaryocyte has to stay on the bone marrow side. Discher and his colleagues recently examined what size pores different types of bone marrow cells could slip through, and they found that megakaryocytes had trouble squeezing through even the largest openings, probably because of their chromosomepacked nuclei. “If you ask me why this cell is polyploid, I’d say it helps anchor the body of the cell in the marrow,” says Discher, whose team reported its findings in the 19 Novem-
726
multiple chromosome copies (blue) have sorted into three clusters in preparation for cell division.
existing cells might cause less disruption than producing more cells through division, which requires that a cell disengage from its neighbors, notes cell biologist Brian Calvi of Indiana University, Bloomington. Yet for one mammalian cell type that takes polyploidy to the extreme, work by Leone’s team downplays the size connection. Cells in the outer layer of embryos, known as trophoblast giant cells, are polyploidy champions—in mice they pack up to 1000 genome copies. The cells help the embryo implant in its mother’s womb, and researchers have suggested that adding chromosomes allows the cells to quickly enlarge, enabling the embryo to infiltrate the uterine lining. Leone and his colleagues deleted genes for polyploidy-promoting proteins from trophoblast giant cells in mice, anticipating that embryos would die because implantation would suffer. “We were expecting that polyploidy is really significant,” Leone says. Although the giant trophoblast cells were smaller than normal and carried fewer chromosomes, the mouse embryos lived and grew up into seemingly healthy adults, the researchers reported in Nature Cell Biology in 2012.
14 FEBRUARY 2014
stem cell biologist Thomas Braun of the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, and colleagues examined genetically altered mice whose muscle cells—including those in the heart— were missing a gene that spurs polyploidy. Although the gene’s absence didn’t make all the animals’ heart cells diploid, it did reduce the number of chromosome sets they contained by about one-third. “At baseline conditions, they are pretty normal,” Braun says of the mice. However, deficiencies appeared when the rodents had to cope with setbacks such as a heart attack. The hearts of animals with reduced polyploidy pumped less blood after an induced heart attack than did the hearts of control animals, the group reported in Circulation Research. How polyploidy enables the heart to rebound remains unclear, Braun says. The work by Duncan and his colleagues on liver cells also backs the stress-response hypothesis. Unlike most mammalian organs, the liver has a remarkable ability to regenerate after injury. The liver is also well stocked with polyploid cells: In humans, about 50% of the liver cells called hepatocytes carry extra sets of chromosomes. Duncan’s team had originally explored
VOL 343 SCIENCE www.sciencemag.org Published by AAAS
CREDIT: (RIGHT) ANDREW W. DUNCAN AND MARKUS GROMPE
Bonus DNA. The polyploid cells in mammalian bodies differ in their location, function, and number of chromosome sets (table). In a liver cell (right), the
CREDIT: A. DUNCAN ET AL., GASTROENTEROLOGY 6 (JANUARY 2012) © 2012 AGA INSTITUTE, PUBLISHED BY ELSEVIER INC.
NEWSFOCUS whether the polyploid cells within the liver are “terminally differentiated,” meaning that they had become mature cells that don’t divide and help replenish the organ. So the team transplanted polyploid hepatocyte cells into mice whose livers had been partially removed. “To our great surprise, they regenerated the liver perfectly,” Duncan says. That’s when Duncan put the liver cells under the microscope, turned on the camera, and noticed their unorthodox division style. The researchers discovered something else unusual about the cells. As the team revealed in Nature in 2010, when many of the polyploid cells divided, they spawned diploid daughter cells. But often these diploid daughters hadn’t quite returned to normal—many of them had gained or lost an individual chromosome, a condition called aneuploidy that is generally considered ominous. “Most cancer folks will Double down. The chromosome copies from a polyploid liver cell arranged by size, showing that the cell tell you that aneuploidy is synonymous with carries four copies of almost every one. cancer,” Duncan says. But some researchers have proposed their livers were no less able to regrow after who develop it. Mature megakaryocytes that aneuploidy can create useful genetic injury. The mice De Bruin and colleagues don’t divide, but in this form of cancer, the diversity in a tissue or organ, allowing cells studied, for example, could restore their livers cells remain immature, don’t become polyto add a copy of a beneficial gene or throw after surgical removal of two-thirds of the ploid, and replicate prodigiously, causing out a copy of a detrimental one. And when organ. “This polyploidization does not have the leukemia. Crispino and colleagues proDuncan and colleagues studied an example an effect on regeneration or on proliferation pose that forcing the cells to become polyof liver regeneration in mice, they found that rate,” De Bruin says. ploid and mature might treat the cancer. sites where regrowth occurred were rich in The work from both teams also underThe team revealed in Cell in 2012 that aneuploid cells. They have discovered that mines another older polyploidy hypothesis. it had identified more than 200 compounds aneuploid cells are abundant in human The liver, De Bruin notes, “is all the time that, in lab dishes, spur polyploidy in livers, too. human megakaryocytes. One Duncan now hypothesizes of these molecules, alisertib, that polyploidy in the liver is is already under-going clinical The real unanswered question is why any a roundabout way to produce trials for several other types of aneuploid cells that have cancer—though not because cell type is polyploid. We are poised to regenerative properties. His team of its ability to stimulate begin answering that question. is now working to confirm that polyploidy. Crispino’s group is these cells spur regeneration in now trying to organize an initial —Robert Duronio, University of North Carolina, Chapel Hill people suffering from hepatitis safety trial of the drug in people B, in which a virus devastates the with acute myeloid leukemia. liver. Some patients die unless they get a liver exposed to toxins.” Hepatocytes work hard Although polyploidy research has recorded transplant, but others survive as sections of to detoxify all those noxious substances, some progress in recent years, the field still the organ regenerate. The researchers are and some researchers had speculated that hasn’t nailed down the benefits polyploidy collecting tissue samples to determine if their extra genetic material could boost the provides to different mammal cell types. areas of the liver that regrow are high in output of proteins crucial to this. Yet the mice To move forward, Leone says, researchers aneuploid cells. whose livers had reduced polyploidy had no should take a cue from plant biologists, But the idea that polyploidy helps tissues problems breaking down toxins, De Bruin’s who have tested polyploidy’s advantages in regenerate remains a hypothesis, as findings group found. specific environmental conditions, showing from Leone’s group and that of Alain de that it boosts tolerance for salinity (Science, Bruin, a pathologist and veterinarian at Exploiting polyploidy 9 August 2013, p. 658). Scientists could Utrecht University in the Netherlands, Even as they wrestle with mystery of poly- perform similar studies on liver cells, for emphasize. They genetically engineered mice ploidy, researchers wonder whether they example, by gauging whether polyploidy so the animals’ livers lack two polyploidy- can put what they’ve learned to use. Leu- helps them deal with different diets. Delving promoting proteins. “We can generate a kemia biologist John Crispino of North- further into polyploidy’s cellular roles will mouse whose liver is almost entirely [diploid] western University’s Feinberg School of probably produce some surprises, UNC cells,” De Bruin says. Both teams expected Medicine in Chicago, Illinois, and his col- Chapel Hill’s Duronio predicts. “There are that the animals would suffer ill effects. leagues have trained their sights on a type going to be many uses for polyploidy, and Instead, the mice were vigorous, each group of acute myeloid leukemia, triggered by we are just scratching the surface.” reported in Nature Cell Biology in 2012, and megakaryocytes, that kills most adults –MITCH LESLIE www.sciencemag.org SCIENCE VOL 343 Published by AAAS
14 FEBRUARY 2014
727
